The CD30 cell surface molecule is a member of the tumor necrosis factor receptor (TNF-R) superfamily. This family of molecules has variable homology among its members and includes nerve growth factor receptor (NGFR), CD120(a), CD120(b), CD27, CD40 and CD95. These molecules are typically characterized by the presence of multiple cysteine-rich repeats in the extracytoplasmic region (see, e.g., de Bruin et al., 1995, Leukemia 9:1620-1627). Members of this family are believed to be involved in the regulation of the proliferation and differentiation of lymphocytes.
CD30 is a type I transmembrane glycoprotein with six (human) or three (murine and rat) cysteine-rich repeats with a central hinge sequence. CD30 exists as a 120 kDa membrane molecule. It is shed from the cell surface as a soluble protein (sCD30) of approximately 90 kDa. Shedding of sCD30 occurs as an active process of viable CD30 cells. cDNAs encoding the CD30 protein have been cloned from expression libraries using monoclonal antibodies Ki-1 and Ber-H2 (see, e.g., Schwab et al., 1982, Nature 299:65). The mouse and rat CD30 cDNAs have been found to encode 498 and 493 amino acids, respectively. Human CD30 cDNA encodes an additional 90 amino acids, partially duplicated from one of the cysteine rich domains. The CD30 gene has been mapped to 1p36 in humans and 5q36.2 in rats.
CD30 is preferentially expressed by activated lymphoid cells. Stimulation of CD30 in lymphoid cells has been shown to induce pleiotropic biological effects, including proliferation, activation, differentiation and cell death, depending on cell type, stage of differentiation and presence of other stimuli (see, e.g., Grass et al., 1994, Blood 83:2045-2056).
CD30 is expressed on a subset of non-Hodgkin's lymphomas (NHL), including Burkitt's lymphoma, anaplastic large-cell lymphomas (ALCL), cutaneous T-cell lymphomas, nodular small cleaved-cell lymphomas, lymphocytic lymphomas, peripheral T-cell lymphomas, Lennert's lymphomas, immunoblastic lymphomas, T-cell leukemia/lymphomas (ATLL), adult T-cell leukemia (T-ALL), and centroblastic/centrocytic (cb/cc) follicular lymphomas (Stein et al., 1985, Blood 66:848; Miettinen, 1992, Arch. Pathol. Lab. Med. 116:1197; Pins et al., 1990, Histopathology 17:211; Burns et al., 1990, Am. J. Clin. Pathol. 93:327; and Eckert et al., 1989, Am. J. Dermatopathol. 11:345). CD30 expression has also been reported on several virally-transformed lines such as human T-Cell Lymphotrophic Virus I or II transformed T-cells, and Epstein-Barr Virus transformed B-cells (Stein et al, 1985, Blood 66:848; Andreesen et al, 1984, Blood 63:1299). CD30 expression has been documented in embryonal carcinomas, nonembryonal carcinomas, malignant melanomas, mesenchymal tumors, and myeloid cell lines and macrophages at late stages of differentiation (Schwarting et al., 1989, Blood 74:1678; Pallesen et al, 1988, Am J. Pathol. 133:446; Mechtersheimer et al, 1990, Cancer 66:1732; Andreesen et al., 1989, Am. J. Pathol. 134:187).
CD30 expression also has been reported to increased or altered in a variety of autoimmune and inflammatory diseases, including atopic allergy (atopic dermatitis, atopic asthma, rhinoconjunctivitis, allergic rhinitis), systemic lupus erythematosus, systemic sclerosis (scleroderma), graft versus host disease (GVHD), HIV and EBV infection, measles, Omenn's syndrome, ulcerative colitis, rheumatoid arthritis, multiple sclerosis, psoriasis, Hashimoto's thyroiditis, primary biliary cirrhosis, Sjogren's syndrome, Wegener's granulomatosis, and tuberculosis (Gruss et al., 1997, Immunol. Today 18:156-163; Hone and Watababe, 1998, Sem. Immunol. 10:457-470; Bengtsson, 2001, Allergy 56:593-603; Gerli et al., 2001, Trends Immunol. 22:72-77).
Murine anti-CD30 mAbs have been generated by immunization of mice with HD cell lines or purified CD30 antigen. Such antibodies include AC10, originally termed C10 (Bowen et al, 1993. J. Immunol. 151:5896-5906), HeFi-1 (Hecht et al, 1985, J. Immunol. 134:4231-4236); and BerH2 (Schwarting et al., 1989, Blood 74:1678-1689). However, murine antibodies do not constitute ideal therapeutic agents for humans.
There remains a need, therefore, for additional therapeutic agents directed to CD30. More specifically, there exists a need for humanized antibodies specific to CD30, because of their potential as therapeutic agents in the treatment of diseases associated with CD30 expressing cells.